Idiopathic pulmonary fibrosis (IPF) kills about 40,000 persons in the United States each year. There are currently around 100,000 Americans afflicted with this fatal disease that typically results in death within 5 years. This year alone another approximately 50,000 Americans will receive this devastating diagnosis. While two recently approved drugs reduce the time to decline in certain lung parameters, and the risk for acute exacerbations, there is no currently available approach, beyond lung transplantation, that has been proven to extend the lives of IPF patients. Our ultimate goal is to improve the lives of patients faced with this grim prognosis by developing a safe and effective, inhalable therapeutic to halt, and possibly reverse, the fibrotic process underlying IPF pathogenesis. We have identified the redox-regulating enzyme, glutaredoxin 1 (Grx1), as a promising therapeutic candidate. Our studies using the well-established bleomycin and TGF- lung fibrosis models in mice have demonstrated that: (1) Grx1 knockout mice develop markedly more severe lung damage than control mice; (2) mice that overexpress Grx1 in epithelial cells are protected from fibrosis; and (3) aerosol delivery of recombinant Grx1 reverses multiple parameters of lung pathology even in aged mice, and even when administered after establishment of fibrotic alterations. As Grx1 is highly conserved in all mammals, we anticipate that human recombinant Grx1 will have similar effects. Our development plan includes a collaboration with Pulmatrix, Inc., a company with a proven track record for incorporating large molecules into their proprietary iSPERSE dry powder formulation, and advancing clinical development of such for serious respiratory conditions like cystic fibrosis. In Phase I of this application we propose to produce a murine recombinant Grx1 iSPERSE proprietary dry-powder formulation (iSPERSE, Pulmatrix, Inc.) and optimize both process conditions and excipients. We will then perform in vitro and in vivo testing to confirm equivalence and determine the maximum tolerated dose (MTD) in mice. In Phase II, we will complete murine efficacy studies and then identify, develop and characterize a lead formulation for the clinical grade product - a human Grx1 iSPERSE dry powder formulation, and conduct nonclinical safety and toxicity studies with this product in rats and monkeys. Upon successful completion of non-clinical safety and toxicity studies, we will submit an IND to pursue clinical studies with our novel inhalable product. The successful development of inhalable human Grx1 iSPERSE would result in an entirely new approach to treat IPF. This application describes the work necessary to complete preclinical development, and will position Grx1 iSPERSE for initial clinical trials.